Evaluating pirtobrutinib for the treatment of relapsed or refractory mantle cell lymphoma

ABSTRACT

Introduction

Mantle cell lymphoma (MCL) is an uncommon non-Hodgkinlymphoma that is generally considered incurable. Covalent BTK inhibitors (cBTKi)are the cornerstone of treatment for relapsed or refractory (R/R) MCL, buttreatment options are limited and prognosis is poor after cBTKi failure.Pirtobrutinib is a non-covalent BTK inhibitor that has demonstrated excellentefficacy and safety and represents an important new treatment in the evolvingtreatment landscape of R/R MCL.

Areas covered

This review will provide an overview of the therapeuticlandscape of R/R MCL, characteristics of pirtobrutinib, and efficacy and safetydata of pirtobrutinib in R/R MCL from pivotal clinical trials. PubMed and majorhematology conference proceedings were searched to identify relevant studiesinvolving pirtobrutinib.

Expert opinion

For patients with R/R MCL that has progressed aftertreatment with cBTKi, pirtobrutinib is an important and efficacious treatmentthat confers favorable outcomes. In the post-cBTKisetting, when chimeric antigen receptor (CAR) T-cell therapy is not availableor feasible, pirtobrutinib is the preferred treatment for R/R MCL. How tosequence or combine pirtobrutinib with CAR T-cell therapy and other availableor emerging therapies requires further investigation. Future studies shouldalso explore the role of pirtobrutinib inearlier lines of therapy for MCL.

KEYWORDS:

• Mantle cell lymphoma
• relapsed and/or refractory
• Bruton tyrosine kinase inhibitor
• pirtobrutinib
• chimeric antigen receptor T-cell therapy

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Article highlights

• Mantle cell lymphoma (MCL) is an uncommon, generally incurable form of non-Hodgkin lymphoma that is characterized by t(11;14) translocation and associated with unfavorable prognosis.

• The current preferred treatment for relapsed/refractory (R/R) MCL is a covalent BTK inhibitor (cBTKi), but treatment options are limited and prognosis is poor after failure of cBTKi.

• Pirtobrutinib is a highly selective, non-covalent, reversible BTK inhibitor that can bind and inhibit both wild type and C481S mutant BTK variants.

• In the BRUIN trial, pirtobrutinib demonstrated excellent safety and efficacy in R/R B-cell malignancies, particularly in CLL/SLL and MCL.

• In cBTKi-exposed R/R MCL, pirtobrutinib demonstrated an objective response rate of approximately 50%, with a median duration of response of approximately 21 months and a median overall survival of approximately 24 months.

• Pirtobrutinib compares favorably to historical therapies in the post-cBTKi setting and is an important treatment option in the evolving treatment landscape of R/R MCL.

• Future studies will investigate how to sequence and/or combine pirtobrutinib with chimeric antigen receptor T-cell therapy and emerging novel therapies, and will examine the role of pirtobrutinib in earlier lines of therapy.

Declaration of interest

Y Wang has received research funding paid to their institution from Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, and Genmab, and honorarium paid to their institution from Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, Genmab, and AbbVie for advisory board participation, consultancy, or scientific presentation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Company review

Eli Lilly provided a scientific accuracy review at the request of the journal editor.

Additional information

Funding

This paper was not funded.